Katsumi Amikura1, Seiki Matsuno, Shinichi Egawa. 1. First Department of Surgery, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Abstract
PURPOSE: We investigated the potentiation of combination therapy using tumor necrosis factor (TNF) with TNP-470, a potent angiogenesis inhibitor. METHODS: We evaluated the antitumor effect in vivo against subcutaneous (s.c.) MC38 mouse colon adenocarcinoma tumors in C57BL/6 mice. The mice were treated with a single bolus injection via the tail vein of 3 or 8 microg rhTNF in 0.5% bovine serum albumin/normal saline (BSA/NS), or with 0.5% BSA/NS alone as a control, with or without TNP-470 pretreatment, given as 30 or 60 mg/kg x 2 days, s.c. DNA synthesis in human umbilical endothelial cells (HUVEC) was assessed by [(3)H]thymidine uptake after incubation with TNF, with or without TNP-470. RESULTS: The antitumor effect of TNP-470 pretreatment combined with 3 microg recombinant human (rh) TNF injection resulted in an 80% reduction of tumor volume compared with the control. This was significantly better than that induced by 3 microg rhTNF alone (P < 0.005). DNA synthesis in HUVEC was inhibited by TNF with TNP-470 in a dose-dependent manner, but there was no enhanced effect against MC38 in vitro. CONCLUSIONS: These results suggest that the combination of the angiogenesis inhibitor TNP-470 and TNF might have a synergistic antitumor effect on solid tumors in vivo.
PURPOSE: We investigated the potentiation of combination therapy using tumor necrosis factor (TNF) with TNP-470, a potent angiogenesis inhibitor. METHODS: We evaluated the antitumor effect in vivo against subcutaneous (s.c.) MC38 mousecolon adenocarcinoma tumors in C57BL/6 mice. The mice were treated with a single bolus injection via the tail vein of 3 or 8 microg rhTNF in 0.5% bovine serum albumin/normal saline (BSA/NS), or with 0.5% BSA/NS alone as a control, with or without TNP-470 pretreatment, given as 30 or 60 mg/kg x 2 days, s.c. DNA synthesis in human umbilical endothelial cells (HUVEC) was assessed by [(3)H]thymidine uptake after incubation with TNF, with or without TNP-470. RESULTS: The antitumor effect of TNP-470 pretreatment combined with 3 microg recombinant human (rh) TNF injection resulted in an 80% reduction of tumor volume compared with the control. This was significantly better than that induced by 3 microg rhTNF alone (P < 0.005). DNA synthesis in HUVEC was inhibited by TNF with TNP-470 in a dose-dependent manner, but there was no enhanced effect against MC38 in vitro. CONCLUSIONS: These results suggest that the combination of the angiogenesis inhibitor TNP-470 and TNF might have a synergistic antitumor effect on solid tumors in vivo.
Authors: M Clauss; J C Murray; M Vianna; R de Waal; G Thurston; P Nawroth; H Gerlach; R Bach; P C Familletti; D Stern Journal: J Biol Chem Date: 1990-04-25 Impact factor: 5.157
Authors: M Clauss; M Gerlach; H Gerlach; J Brett; F Wang; P C Familletti; Y C Pan; J V Olander; D T Connolly; D Stern Journal: J Exp Med Date: 1990-12-01 Impact factor: 14.307